炭疽致死因子抑制剂的研究

发布时间：2018-03-23 10:39

  本文选题：炭疽　切入点：炭疽致死因子　出处：《广西医科大学》2017年硕士论文

【摘要】：炭疽是由炭疽芽孢杆菌(Bacillus anthracis)引起的恶性传染病,是世界上最危险的三大生化武器之一(其它两种是天花病毒和沙林)。炭疽杆菌主要通过释放炭疽毒素使宿主致病,因此炭疽毒素是炭疽感染导致死亡的重要原因。炭疽毒素包括三种毒力因子:保护性抗原(Protective antigen,PA),致死因子(Lethal factor,LF)和水肿因子(Edema factor,EF)。PA和EF装配成水肿毒素、PA和LF装配成致死毒素。其中保护性抗原不参与毒理作用,它的作用是介导其他两种毒力因子进入细胞。EF/LF在胞内释放并发挥酶活性而引起细胞死亡。针对这一机理,有三种可能的治疗策略:1)阻断PA与受体的结合;2)阻断毒素的装配;3)抑制LF和EF的酶活性。迄今为止还没有能够抗炭疽毒素中毒的药物。由于致死因子是炭疽毒素的主要毒力因子。因此,研究炭疽致死因子抑制剂,进而开发抗炭疽致死毒素药物,是关乎国家安全稳定的迫切需要。在前期研究中,我们根据炭疽致死因子的结构特征,结合国际在研的活性化合物,进行了致死因子抑制剂的设计、合成和活性评价工作,建立了从分子、细胞到动物模型的抗炭疽毒素化合物的评价方法获得了在动物体内具有显著抗炭疽致死毒素的化合物。在此基础上,我们分析每个化合物结构特征,进一步设计了一系列新结构的目标化合物。对这些目标化合物的合成设计了五条合成路线,利用这些合成路线共合成了47个目标化合物分子。这些化合物尚未见文献报道,其结构都通过了1H-NMR、LC-MS的确证。在目标化合物的合成过程中,对反应条件都进行了比较详细的探索,尤其对各个中间体的合成,都找到了适合于本课题的合成方法。利用荧光多肽裂解试验测定目标化合物对LF裂解MAPPKide多肽的抑制活性。结果表明:对炭疽致死因子(LF)的抑制活性,百分抑制率大于阳性药的有Ⅰ-1、Ⅰ-6、Ⅱ-1、Ⅱ-3、Ⅱ-6、Ⅱ-7、Ⅲ-1、Ⅲ-4、Ⅲ-6、Ⅲ-7、Ⅲ-8、Ⅲ-13、Ⅳ-1、Ⅳ-2、Ⅳ-3、Ⅳ-4、Ⅳ-5、Ⅳ-6、Ⅳ-7、Ⅳ-9、Ⅳ-11和Ⅴ-4二十二个化合物;百分抑制率接近阳性药的有Ⅲ-3、Ⅲ-5和Ⅲ-12三个化合物;百分抑制率小于阳性药的有Ⅰ-2、Ⅰ-3、Ⅰ-4、Ⅰ-5、Ⅰ-7、Ⅱ-2、Ⅱ-4、Ⅱ-5、Ⅱ-8、Ⅱ-9、Ⅱ-10、Ⅱ-11、Ⅲ-2、Ⅲ-9、Ⅲ-10、Ⅲ-11、Ⅳ-8、Ⅳ-10、Ⅳ-12、Ⅴ-1、Ⅴ-2和Ⅴ-3二十二个化合物。根据初步活性评价实验结果,对每一类目标化合物进行了构效关系的初步分析,为进一步对这些化合物的结构改造以及活性评价奠定了一定的基础。
[Abstract]:Anthrax is composed of Bacillus anthracis (Bacillus anthracis) caused by infectious diseases, is one of the three chemical weapons the most dangerous in the world (the other two kinds of smallpox and anthrax sarin). Mainly through the release of anthrax toxin to host pathogens, so the anthrax toxin is an important cause of death of anthrax infection. Including anthrax toxin three kinds of virulence factors: protective antigen (Protective, antigen, PA), (Lethal factor, LF lethal factor) and edema factor (Edema factor, EF.PA) and EF assembly PA edema toxin, and LF assembly. The lethal toxin protective antigen is not involved in the toxicity, its role is mediated by the other two kinds of virulence factors into the cells of.EF/LF in intracellular release and activity caused by cell death. According to this mechanism, there are three possible treatment strategies: 1) blocking PA binding to the receptor; 2) blocking toxin suppression assembly; 3) Enzyme activity LF and EF. So far there is no drug resistance to anthrax toxin poisoning. The lethal factor is a major virulence factor of anthrax toxin. Therefore, the research and development of anthrax lethal factor inhibitor, anti anthrax lethal toxin drug, is an urgent need for national security and stability. In our previous study, we according to the structure the characteristics of anthrax lethal factor, combined with the international active compounds in research, design of lethal factor inhibitor, synthesis and activity evaluation, established from molecular, cell to evaluation of anthrax toxin compounds in animal models obtained compounds with significant anti anthrax lethal toxin in the animal. On this basis, we analysis of each compound structure, we design a series of new compounds structure. The synthesis of these compounds has designed five synthesis 璺�绾�,鍒╃敤杩欎簺鍚堟垚璺�绾垮叡鍚堟垚浜�47涓�鐩�鏍囧寲鍚堢墿鍒嗗瓙.杩欎簺鍖栧悎鐗╁皻鏈�瑙佹枃鐚�鎶ラ亾,鍏剁粨鏋勯兘閫氳繃浜，

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